The goal of this project is to conduct translational research aimed at developing improved and novel therapies for children with HIV infection and HIV-associated malignancies. In terms of HIV infection, both antiretroviral and immunologic approaches are currently being investigated. A major new protocol opened in the past year. This protocol investigates the use of a new, nucleotide analog reverse transcriptase inhibitor in pediatric patients who have failed therapy with several other antiretroviral agents. The study aims to obtained the pharmacokinetic and safety data needed to use the drug in the pediatric population. The study also aims to investigate several important aspects of pediatric HIV pathogenesis, such as the ability of highly experienced pediatric patients infected with resistant virus to respond new rounds of therapy and the potential for immune reconstitution in those patients, the development and evolution of antiviral resistance in pediatric patients, and strategies for optimizing pediatric HIV therapy, particularly for highly experienced patients. We continue to study the long-term virological and immunological effects of highly active antiretroviral therapy including a protease inhibitor and in particular the ability of such a regimen to effect immune reconstitution. The protease inhibitors have been used in children at the NCI longer than anywhere else and this ongoing experience may prove important for assessing the very long term response to highly active antiretroviral therapy in children. Results suggest that some patients on long-term therapy have immunologic improvement without sustained drops in their viral load. We have also recently completed studies of two novel immunomodulatory agents in HIV-infected children: recombinant IL-2 and HIV-1 immunogen vaccine. In addition to delineation of toxicity and antiviral activities, an intensive focus is directed toward assessment of quantitative and qualitative measures of immune function associated with these therapies. Administration of rIL-2 is associated with increases in CD4 cell counts as well as improvements in DTH skin test reactivity. Therapeutic vaccination with HIV-1 immunogen results in development of HIV-specific lymphoproliferative responses to immunogen as well as p24 antigen. A study of ddI (didanosine) and hydroxyurea, stavudine, and efavirenz as a protease-sparing salvage regimen demonstrated decreases in markers of immune activation and increases in CD4 cell counts despite virologic rebound. Analysis of viral resistance studies that may account for these observed effects is ongoing. A study of ddI (didanosine) and hydroxyurea, stavudine, and efavirenz as a protease-sparing salvage regimen demonstrated decreases in markers of immune activation and increases in CD4 cell counts despite virologic rebound. Analysis of viral resistance studies that may account for these observed effects is ongoing. We are also initiating studies examining HPV infection in immunosuppressed patients and the use of Magnetic Resonance Spectroscopy to determine the relationship between brain metabolite levels and neuropsychological functioning. We have developed a protocol to investigate therapeutic drug monitoring (TDM) as a way of optimizing the use of available drugs, and have also developed a protocol to obtain the needed safety and pharmacokinetic data for capravirine, a new non-nucleoside reverse transcriptase inhibitor. As with tenofovir, these studies also include integral studies aimed at understanding the pathogenesis of pediatric HIV disease and the responses that accompany new and effective therapy. Several additional protocols of new antiretroviral agents in children are under development. Longitudinal studies of neurocognitive function, brain imaging and immune measures in children receiving antiretroviral therapy are being conducted in addition to investigation of the pathophysiology of HIV encephalopathy. Psychosocial studies include investigation of correlates of psychosocial functioning and coping strategies in long term survivors who are now transitioning from adolescence to young adulthood, assessment of the relationship between various behaviors, disclosure, and psychosocial outcomes, assessment of compliance to HAART regimens in relation to health belief systems, a comparison between the psychosocial correlates of fathering an HIV-infected child and a child with cancer, and studies of the effects of participating in the Starbright home program in which patients can communicate by computer with sick children in other hospitals around the country.100% AIDS related.